Closure of the neural tube during development is a highly complex but poorly understood process. Not surprisingly, neural tube defects (NTDs) have a multifactorial etiology, including both genetic and environmental factors. The importance of maternal folate status to NTD risk was first suggested more than forty years ago (Hibbard ED & Smithells RW (1965) Lancet 1:1254). Many human studies show that periconceptional intake of supplemental folic acid can reduce the incidence of NTDs by as much as 70% in some populations (Ross ME (2010) Wiley Interdiscip Rev Syst Biol Med 2:471-480). These results led to mandated fortification of all enriched cereal grain products with folic acid in the U.S. beginning in 1996 to ensure that women of child-bearing age would consume adequate quantities of the vitamin. While folic acid fortification has decreased NTD incidence in some subpopulations, fortification has not completely eliminated NTDs (Hobbs C A, et al. (2010) Folate in Health and Disease, ed Bailey LB (CRC Press, Taylor & Francis Group, Boca Raton, Fla.), 2nd Ed, pp 133-153). Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined.